Sublethal Doses ofBacillus anthracisLethal Toxin Inhibit Inflammation with Lipopolysaccharide andEscherichia coliChallenge but Have Opposite Effects on Survival

Abstract

On the basis of the findings of previous in vitro studies, we hypothesized that anthrax lethal toxin (LeTx) would have anti-inflammatory effects in vivo. We investigated the effects of sublethal doses of LeTx in rats receiving intravascular challenge with lipopolysaccharide (LPS) or intratracheal challenge with Escherichia coli. In rats receiving 24-h infusions of LPS, compared with control rats, pretreatment with high or low sublethal doses of LeTx 3 h before infusion produced similar patterns of reduction in the hazards ratio (HR) of survival at 168 h (0.60 [95% confidence interval {CI}, 0.37-0.98]; P=.03, for the doses combined). LeTx increased mean arterial blood pressure throughout the period of LPS infusion (P=.001); decreased the levels of 10 of 13 cytokines assessed (i.e., interleukin [IL]-1 alpha , IL-1 beta , IL-2, IL-4, IL-6, IL-10, interferon- gamma , tumor necrosis factor- alpha , granulocyte macrophage-colony-stimulating factor, migratory inhibitory protein [MIP]-1 alpha , MIP-2, MIP-3 alpha , and RANTES) at 2 h; decreased all 13 cytokine levels at 8 h; decreased only 4 cytokine levels at 24 h; and decreased the plasma level of nitric oxide (NO) at 8 h and 24 h but not at 2 h (P< or =.02, for the effect of LeTx, across time, on both cytokine levels and the NO level). Although pretreatment with LeTx before challenge with E. coli altered mean arterial blood pressure, cytokine levels, and the NO level in a pattern similar to that noted in association with LPS infusion, it increased the HR in a pattern different from that associated with LPS (4.36 [95% CI, 0.3-63.4]; P=.04, for the effects of LeTx with LPS vs. E. coli). Inhibition of inflammation with LeTx can occur in vivo, and, although beneficial with noninfectious stimuli, it may be harmful with bacteria.